Bystander tumoricidal effect and gap junctional communication in lung cancer cell lines.
Tumor cells expressing the herpes simplex virus-thymidine kinase (HSV-tk) gene become sensitive to ganciclovir (GCV), and the phenomenon by which tumor cells surrounding the HSV-tk expressing cells also become sensitive to GCV is known as the "bystander effect." The purpose of this study was to investigate the bystander effect in human lung-cancer cell lines, and the role of gap-junctional intercellular communication as the mechanism responsible for it. Gap-junctional intercellular communication was measured both with a dye-transfer assay involving single-cell microinjection of Lucifer Yellow and with a PKH26/calcein-AM double-dye-transfer assay. Significant bystander tumoricidal effect was observed in lung-cancer cell lines when cultured cells contained only 10% HSV-tk expressing cells. This was also observed to occur with cell lines of different origin or from different species. Although gap-junctional intercellular communication characterized by rapid transfer of Lucifer Yellow was not observed, we did detect gap-junctional communication marked by the slow transfer of calcein-AM in lung-cancer cell lines. However, neither an inhibitor (1-octanol) nor an enhancer (all trans-retinoic acid [ATRA]) of gap-junctional communication affected the extent of the bystander effect. These findings suggest that low levels of gap-junctional communication may be efficient for producing the bystander effect in lung-cancer cells, or that other mechanisms may underlie this effect. Although gap-junctional communication may play an important role in generating the bystander effect in tumor cells expressing the HSV-tk gene, further knowledge of the mechanism of this effect may help improve the treatment of lung cancer with an HSV-tk system.
Imaizumi
K
K
First Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Hasegawa
Y
Y
Kawabe
T
T
Emi
N
N
Saito
H
H
Naruse
K
K
Shimokata
K
K
D020003:1-Octanol / Q000494:pharmacology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002277:Carcinoma / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002472:Cell Transformation, Viral; D018920:Coculture Techniques; D015774:Ganciclovir / Q000494:pharmacology*; D017629:Gap Junctions / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D014212:Tretinoin; D013937:Thymidine Kinase; D020003:1-Octanol; D015774:Ganciclovir